Tetrahydropyran derivatives and their use as therapeutic agents

ABSTRACT

The present invention relates compounds of the formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 15  and R 16  represent a variety of substituents; and pharmaceutically acceptable salts thereof. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migaine, emesis or postherpetic neuralgia.

This invention relates to a class of tetrahydropyran compounds which areuseful as tachykinin antagonists. More particularly, the compounds ofthe invention are useful as neurokinin 1 (NK-1) receptor antagonists.

International (PCT) Patent Publication Nos. WO 00/56727, published28^(th) Sep. 2000, and WO 02/16344, published 28^(th) Feb. 2002,describe classes of tetrahydropyran derivatives and their use as NK-1receptor antagonists. The novel compounds of the present invention arecharacterised by the 5- or 6-membered carbonyl or sulfonyl containingcyclic moiety represented by the R⁷ substituent.

International (PCT) Patent Publication No. WO 03/022839, published20^(th) Mar. 2003 (after the priority date of the present invention),describes a further class of tetrahydropyran derivatives and their useas NK-1 receptor antagonists. The compounds of the present invention arenovel in view of the nature of the substituents at the 4-position on thetetrahydropyran ring.

The present invention provides compounds of the formula (I):

wherein

-   -   R¹ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkyl,        fluoroC₁₋₆alkoxy, C_(3,7)cycloalkyl, C_(3,7)cycloalkylC₁₋₄alkyl,        NO₂, CN, SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b),        C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy,        wherein R^(a) and R^(b) each independently represent hydrogen or        C₁₋₄alkyl;    -   R² is hydrogen, halogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl or        C₁₋₆alkoxy substituted by C₁₋₄alkoxy;    -   R³ is hydrogen, halogen or fluoroC₁₋₆alkyl;    -   R⁴ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkyl,        fluoroC₁₋₆alkoxy, hydroxy, NO₂, CN, SR^(a), SOR^(a), SO₂R^(a),        CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl, C₂₋₆alynyl or C₁₋₄alkyl        substituted by C₁₋₄alkoxy, wherein R^(a) and R^(b) are as        previously defined;    -   R⁵ is hydrogen, halogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl or        C₁₋₆alkoxy substituted by C₁₋₄alkoxy;    -   R⁶ represents hydrogen or a C₁₋₄alkyl group optionally        substituted by a hydroxy group;    -   R⁷ represents a 5- or 6-membered carbonyl or sulfonyl containing        cyclic group comprising from 0 to 3 nitrogen ring atoms, from 0        to 1 oxygen ring atom and from 0 to 1 sulfur ring, wherein said        ring is optionally substituted at any substitutable position by        one or more substituents selected from ═O, halogen, hydroxy,        R¹¹, R¹², SR^(f), SO₂R^(g), COR^(a), CO₂R^(a), CONR⁹R¹⁰,        -ZNR⁹R¹⁰, benzyl, C₁₋₄alkyl, hydroxyC₁₋₄alkyl, fluoroC₁₋₄alkyl,        chloroC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, C₃₋₇cycloalkyl,        C₃₋₇cycloalkylC₁₋₄alkyl, C₃₋₇cycloalkoxy,        C₃₋₇cycloalkoxyC₁₋₄alkyl, C₁₋₄alkoxy, fluoroC₁₋₄alkoxy,        hydroxyC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkoxy, aryl, arylC₁₋₄alkyl        heteroaryl, heteroarylC₁₋₄alkyl or a 5- or 6-membered ring        containing in the ring one oxygen atom or N(C₁₋₆alkyl), wherein        R^(f) is C₁₋₄alkyl or aralkyl or aryl and R^(g) is C₁₋₄alkyl,        aryl, arylC₁₋₄alkyl or NR⁹R¹⁰;    -   R⁸ represents hydrogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl, hydroxy,        C₁₋₆alkoxy, hydroxyC₁₋₆alkyl NR⁹R¹⁰, CONR⁹R¹⁰ or SO₂R^(g);    -   R⁹ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl,        C₃₋₇cycloalkylC₁₋₄alkyl, fluoroC₁₋₄alkyl C₂₋₄alkyl substituted        by a C₁₋₄alkoxy or hydroxyl group, or R⁹ is a five membered or        six membered nitrogen-containing heteroaromatic ring as        previously defined;    -   R¹⁰ is hydrogen or C₁₋₄alkyl, C₃₋₇cycloalkyl,        C₃₋₇cycloalkylC₁₋₄alkyl, fluoroC₁₋₄alkyl or C₂₋₄alkyl        substituted by a C₁₋₄alkoxy or hydroxyl group;    -   or R⁹, R¹⁰ and the nitrogen atom to which they are attached form        a heteroaliphatic ring of 4 to 7 ring atoms, optionally        substituted by one or two groups selected from hydroxy, COR^(e),        CO₂R^(e), C₁₋₄alkyl optionally substituted by a C₁₋₄alkoxy or        hydroxyl group, or C₁₋₄alkoxy optionally substituted by a        C₁₋₄alkoxy or hydroxyl group, or a five membered or six membered        nitrogen-containing heteroaromatic ring as previously defined,        or said heteroaliphatic ring is substituted by a spiro-fused        lactone ring, and said heteroaliphatic ring optionally        containing a double bond, which heteroaliphatic ring may        optionally contain an oxygen or sulphur ring atom, a group S(O)        or S(O)₂ or a second nitrogen atom which will be part of a NH or        NR^(d) moiety, where R^(d) is C₁₋₄alkyl optionally substituted        by hydroxy or C₁₋₄alkoxy;    -   or R⁹, R¹⁰ and the nitrogen atom to which they are attached form        a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;    -   or R⁹, R¹⁰ and the nitrogen atom to which they are attached form        a heteroaliphatic ring of 4 to 7 ring atoms to which is fused a        benzene ring or a five membered or six membered        nitrogen-containing heteroaromatic ring optionally containing 1,        2 or 3 additional heteroatoms selected from N, O and S;    -   R¹¹ and R¹² each independently represent hydrogen, hydroxy,        COR^(e), CO₂R^(e), C₁₋₄alkyl optionally substituted by a        C₁₋₄alkoxy or hydroxyl group, or C₁₋₄alkoxy optionally        substituted by a C₁₋₄alkoxy or hydroxyl group;    -   or, when they are attached to the same carbon atom, R¹¹ and R¹²        may together represent ═O, ═CHCO₂R^(a), —O(CH₂)_(m)O—,        —CH₂O(CH₂)_(k)—, —CH₂OCH₂C(O)—, —CH₂OCH₂CH(OH)—,        —CH₂OCH₂C(CH₃)₂—, —CH₂OC(CH₃)₂CH₂—, —C(CH₃)₂OCH₂CH₂—,        —CH₂C(O)OCH₂—, —OC(O)CH₂CH₂—, —C(O)OCH₂CH₂—, —C(O)OC(CH₃)₂CH₂—,        —C(O)OCH₂C(CH₃)₂—, —OCH₂(CH₂)_(k)—, —OC(CH₃)₂CH₂CH₂—,        —OCH₂C(CH₃)₂CH₂—, —OCH₂CH₂C(CH₃)₂—, —OCH₂CH═CHCH₂—,        —OCH₂CH(OH)CH₂CH₂—, —OCH₂CH₂CH(OH)CH₂—, —OCH₂C(O)CH₂CH₂—,        —OCH₂CH₂C(O)CH₂—, or a group of the formula    -   or, where they are attached to adjacent carbon atoms, R¹¹ and        R¹² may together represent —OCH₂CH₂— or —OCH₂CH(OH)—, or R¹¹ and        R¹² may together form a fused benzene ring;    -   or, R¹¹ and R¹² together form a C₁₋₂alkylene bridge across the        pyrrolidine, piperidine, morpholine or piperazine ring to which        they are attached;    -   R¹³ represents hydrogen, phenyl, benzyl, pyridyl,        tetrahydropyranyl, piperidinyl, N-substituted piperidinyl (where        the N-substituent is C₁₋₆alkyl), C₁₋₄alkyl, C₃₋₇cycloalkyl,        C₃₋₇cycloalkylC₁₋₄alkyl, —SO₂C₁₋₄alkyl or C₂₋₄alkyl substituted        by a C₁₋₄alkoxy or hydroxyl group;    -   R¹⁴ represents hydrogen, halogen, hydroxy, C₁₋₄alkyl,        hydroxyC₁₋₄alkyl or fluoroC₁₋₄alkyl;    -   R¹⁵ and R¹⁶ each independently represent hydrogen, halogen,        C₁₋₆alkyl, CH₂OR^(c), oxo, CO₂R^(a) or CONR^(a)R^(b) where R^(a)        and R^(b) are as previously defined and R^(c) represents        hydrogen, C₁₋₆alkyl or phenyl;    -   Z represents a bond, C₁₋₆alkylene or C₃₋₆cycloalkylene;    -   k is 1, 2 or 3;    -   m is 1 or 2; and    -   n is zero, 1 or 2;    -   with the proviso that when n is zero and R⁸ is hydrogen, R⁷ does        not represent a C-linked nitrogen-containing ring of the formula        wherein    -   A represents NR¹³, and B represents a bond, CH₂, NR¹³ or O,        wherein one or both hydrogen atoms in said CH₂ moiety may be        replaced with one or both of R¹¹ and R¹², or alternatively, one        of the hydrogen atoms in said CH₂ moiety together with a        hydrogen atom from an adjacent carbon are replaced by a double        bond; or A is O, and B is NR¹³; and R¹¹ and R¹² together        represent ═O;        and pharmaceutically acceptable salts thereof.

One particular aspect of the present invention is the class of compoundsof formula (I) and pharmaceutically acceptable salts thereof, wherein

-   -   R⁷ represents a 5- or 6-membered carbonyl or sulfonyl containing        cyclic group comprising from 0 to 3 nitrogen ring atoms, from 0        to 1 oxygen ring atom and from 0 to 1 sulfur ring, wherein said        ring is optionally substituted at any substitutable position by        one or more substituents selected from ═O, halogen, hydroxy,        R¹¹, R¹², SR^(f), SO₂R^(g), COR^(a), CO₂R^(a), CONR⁹R¹⁰,        -ZNR⁹R¹⁰, benzyl C₁₋₄alkyl, hydroxyC₁₋₄alkyl, fluoroC₁₋₄alkyl        chloroC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, C₃₋₇cycloalkyl,        C₃₋₇cycloalkylC₁₋₄alkyl, C₃₋₇cycloalkoxy,        C₃₋₇cycloalkoxyC₁₋₄alkyl, C₁₋₄alkoxy, fluoroC₁₋₄alkoxy,        hydroxyC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkoxy, aryl or arylC₁₋₄alkyl        wherein R^(f) is C₁₋₄alkyl or aralkyl or aryl and R^(g) is        C₁₋₄alkyl, aryl arylC₁₋₄alkyl or NR⁹R¹⁰;    -   R¹³ represents hydrogen, benzyl, C₁₋₄alkyl, C₃₋₇cycloalkyl,        C₃₋₇cycloalkylC₁₋₄alkyl, —SO₂C₁₋₄alkyl or C₂₋₄alkyl substituted        by a C₁₋₄alkoxy or hydroxyl group;        and the remaining groups are as defined above.

A preferred class of compounds of formula (I) is that wherein R¹ ishydrogen, C₁₋₄alkyl C₁₋₄alkoxy, halogen or CF₃.

Another preferred class of compounds of formula (I) is that wherein R²is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

Also preferred is the class of compounds of formula (I) wherein R₃ ishydrogen, fluorine, chlorine or CF₃.

A particularly preferred class of compounds of formula (I) is thatwherein R¹ is fluorine, chlorine or CF₃.

Another particularly preferred class of compounds of formula (I) is thatwherein R² is hydrogen, fluorine, chlorine or CF₃.

Also particularly preferred is the class of compounds of formula (I)wherein R² is hydrogen, fluorine, chlorine or CF₃.

Preferably R¹ and R² are in the 3 and 5 positions of the phenyl ring.

More preferably R¹ is 3-fluoro or 3-CF₃.

More preferably R² is 5-fluoro or 5-CF₃.

More preferably R³ is hydrogen.

Most preferably R¹ is 3-F or 3-CF₃, R² is 5-CF₃ and R₃ is hydrogen.

A further preferred class of compound of formula (I) is that wherein R⁴is hydrogen or fluorine, especially hydrogen.

Another preferred class of compounds of formula (I) is that wherein R⁵is hydrogen, fluorine, chlorine or CF₃.

Preferably R⁴ is hydrogen or 3-fluoro, especially hydrogen, and R⁵ ishydrogen or 4-fluoro.

R⁶ is preferably C₁₋₄alkyl optionally substituted by hydroxy. Inparticular, R⁶ is preferably a methyl or hydroxymethyl group. Mostespecially, R⁶ is a methyl group.

A further preferred class of compounds of formula (I) is that wherein R⁷is a cyclic group selected from the group consisting of:

wherein R¹³ is as previously defined, and further wherein any of saidcyclic groups is optionally substituted by one or more (preferably oneor two) groups as previously defined.

Also preferred is the class of compound of formula (I) wherein R⁷ is acyclic group selected from the group consisting of:

wherein R¹³ is as previously defined, and further wherein any of saidcyclic groups is optionally substituted by one or more (preferably oneor two) groups as previously defined.

Another preferred class of compound of formula (I) is that wherein R⁸ ishydrogen or methyl, and especially hydrogen.

Another preferred class of compounds of formula (I) is that wherein R¹²is hydrogen, hydroxy, C₁₋₂alkyl substituted by hydroxy, C₁₋₄alkoxy(especially methoxy) or CO₂R^(e) (where R^(e) is hydrogen, methyl ethylor benzyl).

A further preferred class of compounds of formula (I) is that whereinR¹² is hydrogen or C₁₋₄alkyl (especially methyl).

Where R¹¹ and R¹² are attached to the same carbon atom they may, inparticular, together represent —C(O)OCH₂CH₂—.

In a further preferred class of compounds of formula (I), R¹³ preferablyrepresents hydrogen, methyl or ethyl.

Another preferred class of compound of formula (I) is that wherein oneof R¹⁵ and R¹⁶ is hydrogen, and especially wherein R¹⁵ and R¹⁶ are bothhydrogen atoms.

A further preferred class of compound of formula (I) is that wherein nis zero or 1, and especially wherein n is zero.

In the definition of the group —NR⁹R¹⁰, R⁹ may aptly be a C₁₋₄alkylgroup or a C₂₋₄alkyl group substituted by a hydroxyl or C₁₋₂alkoxygroup, R¹⁰ may aptly be a C₁₋₄alkyl group or a C₂₋₄alkyl groupsubstituted by a hydroxyl or C₁₋₂alkoxy group, or R⁹ and R¹⁰ may belinked so that, together with the nitrogen atom to which they areattached, they form an azetidinyl, pyrrolidinyl, piperidinyl,morpholino, thiomorpholino, piperazino or piperazino group substitutedon the nitrogen atom by a C₁₋₄alkyl group or a C₂₋₄alkyl groupsubstituted by a hydroxy or C₁₋₂alkoxy group. Particularly preferredheteroaliphatic rings formed by —NR⁹R¹⁰ are azetidine, pyrolidine,piperidine, morpholine, piperazine and N-methylpiperazine, andespecially piperidine.

Where the group NR⁹R¹⁰ represents a heteroaliphatic ring of 4 to 7 ringatoms substituted by two groups, the first substituent, where present,is preferably selected from hydroxy, CO₂R^(e) (where R^(e) is hydrogen,methyl ethyl or benzyl), or C₁₋₂alkyl substituted by hydroxy. Wherepresent, the second substituent is preferably a methyl group. Where twosubstituents are present, said substituents are preferably attached tothe same carbon atom of the heteroaliphatic ring.

Where the group NR⁹R¹⁰ represents a heteroaliphatic ring of 4 to 7 ringatoms substituted by a spiro-fused lactone ring, particularly preferredexamples are:

Where the group NR⁹R¹⁰ represents a heteroaliphatic ring of 4 to 7 ringatoms and said ring contains a double bond, a particularly preferredgroup is 3-pyrroline.

Where the group NR⁹R¹⁰ represents a non-aromatic azabicyclic ringsystem, such a system may contain between 6 and 12, and preferablybetween 7 and 10, ring atoms. Suitable rings include5-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.2.1]heptyl,6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl,6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl,6-azabicyclo[3.3.2]decyl, 7-azabicyclo[4.3.]decyl,7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.

Where the group NR⁹R¹⁰ represents a heteroaliphatic ring of 4 to 7 ringatoms to which is fused a benzene ring or a five membered or sixmembered nitrogen-containing heteroaromatic ring ring optionallycontaining 1, 2 or 3 additional heteroatoms selected from N, O and S,said heteroaromatic ring is preferably a five-membered ring, inparticular a pyrrole, imidazole or triazole ring, a nitrogen atom ofwhich is preferably included in the heteroaliphatic ring. Suitableexamples of such fused ring systems include

Particularly suitable moieties NR⁹R¹⁰ include those wherein NR⁹R¹⁰ isamino, methylamino, dimethylamino, diethylamino, azetidino, pyrrolidino,piperidino, morpholino and piperazino.

Favourably Z is a bond or contains 1 to 4 carbon atoms and mostfavourably 1 to 2 carbon atoms. A particularly favourable group Z is—CH₂—. The group -ZNR⁹R¹⁰, as a substituent on a heteroaromatic ring, ispreferably CH₂N(CH₃)₂.

One favoured group of compounds of the present invention are of theformula (Ia) and pharmaceutically acceptable salts thereof:

wherein

-   -   A¹ is fluorine or CF₃;    -   A² is fluorine or CF₃;    -   A³ is fluorine or hydrogen;    -   A⁴ is fluorine or hydrogen;    -   A⁵ is methyl; and    -   R⁷ and n are as defined in relation to formula (I).

When any variable occurs more than one time in formula (I) or in anysubstituent, its definition on each occurrence is independent of itsdefinition at every other occurrence.

As used herein, the term “alkyl” or “alkoxy” as a group or part of agroup means that the group is straight or branched. Examples of suitablealkyl groups include methyl, ethyl n-propyl, i-propyl n-butyl, s-butyland t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

As used herein, the terms “fluoroC₁₋₆alkyl” and fluoroC₁₋₆alkoxy” meansa C₁₋₆alkyl or C₁₋₆alkoxy group in which one or more (in particular, 1to 3) hydrogen atoms have been replaced by fluorine atoms. Similarly,the term “fluoroC₁₋₄alkyl” means a C₁₋₄alkyl group in which one or more(in particular 1 to 3) hydrogen atoms have been replaced by fluorineatoms. Particularly preferred are fluoroC₁₋₃alkyl and fluoroC₁₋₃alkoxygroups, for example, CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, OCF₃, OCH₂CH₂F,OCH₂CHF₂ or OCH₂CF₃, and most especially CFs, OCFA and OCH₂CF₃.

The cycloalkyl groups referred to herein may represent, for example,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitablecycloalkylalkyl group may be, for example, cyclopropylmethyl.

Similarly cycloalkoxy groups referred to herein may represent, forexample, cyclopropoxy or cyclobutoxy.

As used herein, the terms “alkenyl” and “alkynyl” as a group or part ofa group means that the group is straight or branched. Examples ofsuitable alkenyl groups include vinyl and allyl. A suitable alkynylgroup is propargyl.

As used herein, the term “aryl” as a group or part of a group means anaromatic radical such as phenyl, biphenyl or naphthyl, wherein saidphenyl, biphenyl or naphthyl group may be optionally substituted by one,two or three groups independently selected from halogen, C₁₋₆alkyl,C₁₋₆alkoxy, fluoroC₁₋₆alkyl, fluoroC₁₋₆alkoxy, NO₂, cyano, SR^(a),SOR^(a), SO₂R^(a), COR^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₄alkoxyC₁₋₄alkyl or —O(CH₂)_(m)O—. Preferably saidphenyl, biphenyl or naphthyl group is optionally substituted by one ortwo substituents, especially none or one. Particularly preferredsubstituents include fluorine, chlorine, bromine, C₁₋₄alkyl (especiallymethyl), C₁₋₄alkoxy (especially methoxy), trifluoromethyl,trifluormethoxy or vinyl.

Reference herein to “an optionally substituted five or six-memberednitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3additional heteroatoms selected from N, O and S”, is preferablyreference to a heteroaromatic ring is selected from pyrrole, pyridine,pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole,pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole,triazine, and tetrazole.

Suitable 5- or 6-membered cyclic ethers include optionally substitutedtetrahydropyran and tetrahydrofuran rings.

When used herein the term “halogen” means fluorine, chlorine, bromineand iodine. The most apt halogens are fluorine and chlorine of whichfluorine is preferred, unless otherwise stated.

In a further aspect of the present invention, the compounds of formula(I) may be prepared in the form of a pharmaceutically acceptable salt,especially an acid addition salt.

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable acid such as hydrochloric acid, fumaricacid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid,citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl alkenyl, alkynyl or aralkyl moiety. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g. sodium or potassium salts; and alkalineearth metal salts, e.g. calcium or magnesium salts.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion exchange resin.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the “parent drug” or “parent molecule”)that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionality.

The present invention includes within its scope solvates of thecompounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention have at least three asymmetriccentres, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The preferred compounds of the formula (I) and (Ia) will have thestereochemistry of the 3-, 4- and 5-positions as shown in formulae (Ib)and (Ic)

It will be appreciated that the preferred definitions of the varioussubstituents recited herein may be taken alone or in combination and,unless otherwise stated, apply to the generic formula for compounds ofthe present invention as well as to the preferred classes of compoundrepresented by formula (Ia), formula (Ib) and formula (Ic).

The present invention further provides pharmaceutical compositionscomprising one or more compounds of formula (I) in association with apharmaceutically acceptable carrier or excipient.

Preferably the compositions according to the invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,solutions or suspensions, or suppositories, for oral, parenteral orrectal administration, or administration by inhalation or insufflation.Oral compositions such as tablets, pills, capsules or wafers areparticularly preferred.

A more detailed description of pharmaceutical compositions that aresuitable for the formulation of compounds of the present invention isdisclosed in U.S. Pat. No. 6,071,927, the content of which isincorporated herein by reference (see in particular, column 8, line 50to column 10, line 4).

The present invention further provides a process for the preparation ofa pharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity. Acomprehensive listing of clinical conditions, uses and methods oftreatment for which the compounds of the present invention will beuseful is disclosed in U.S. Pat. No. 6,071,927, the content of which isincorporated herein by reference (see, in particular, column 10, line 14to column 22, line 18).

In particular, the compounds of the present invention are useful in thetreatment of a variety of disorders of the central nervous system. Suchdisorders include mood disorders, such as depression or moreparticularly depressive disorders, for example, single episodic orrecurrent major depressive disorders and dysthymic disorders, or bipolardisorders, for example, bipolar I disorder, bipolar II disorder andcyclothymic disorder; and anxiety disorders, such as panic disorder withor without agoraphobia, agoraphobia without history of panic disorder,specific phobias, for example, specific animal phobias, social phobias,obsessive-compulsive disorder, stress disorders including post-traumaticstress disorder and acute stress disorder, and generalised anxietydisorders.

The compounds of the present invention are also particularly useful inthe treatment of nociception and pain. Diseases and conditions in whichpain predominates, include soft tissue and peripheral damage, such asacute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletalpain, particularly after trauma, spinal pain, myofascial pain syndromes,headache, migraine, episiotomy pain, and burns.

The compounds of the present invention are also particularly useful inthe treatment of respiratory diseases, particularly those associatedwith excess mucus secretion, such as chronic obstructive airwaysdisease, bronchopneumonia, chronic bronchitis, cystic fibrosis andasthma, adult respiratory distress syndrome, and bronchospasm; in thetreatment of inflammatory diseases such as inflammatory bowel disease,psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritisand sunburn; and in the treatment of allergic disorders such as eczemaand rhinitis.

The compounds of the present invention are also particularly useful inthe treatment of gastrointestinal (GI) disorders, including inflammatorydisorders and diseases of the GI tract such as ulcerative colitis,Crohn's disease and irritable bowel syndrome.

The compounds of the present invention are also particularly useful inthe treatment of emesis, including acute, delayed or anticipatoryemesis, such as emesis induced by chemotherapy, radiation, toxins,pregnancy, vestibular disorders, motion, surgery, migraine, andvariations in intercranial pressure. Most especially, the compounds offormula (I) are of use in the treatment of emesis induced byantineoplastic (cytotoxic) agents, including those routinely used incancer chemotherapy; by radiation including radiation therapy such as inthe treatment of cancer; and in the treatment of post-operative nauseaand vomiting.

The excellent pharmacological profile of the compounds of the presentinvention offers the opportunity for their use in therapy at low dosesthereby minimising the risk of unwanted side effects.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day.

For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

In the treatment of emesis, a suitable dosage level is about 0.001 to 10mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially0.01 to 3 mg/kg per day. The compounds may be administered on a regimenof 1 to 4 times per day, preferably once or twice per day.

In the treatment of psychiatric disorders, a suitable dosage level isabout 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg perday, and especially 0.01 to 3 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

It will be appreciated that the amount of a compound of formula (1)required for use in any treatment will vary not only with the particularcompounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

As used herein, the term “treatment” includes prophylactic use toprevent the occurrence or recurrence of any of the aforementionedconditions.

According to a general process (A), compounds of formula (I), in whichR⁷ is an N-linked cyclic group, may be prepared by the reaction of acompound of formula (II)

with an amine of the formula HNR⁹R¹⁰ in the presence of a reducingagent, for example, sodium triacetoxyborohydride or sodiumcyanoborohydride. The reaction is conveniently effected in a suitablesolvent such as a halogenated hydrocarbon, for example,1,2-dichloroethane, conveniently at about room temperature.

Compounds of formula II) may be prepared by oxidation of a compound offormula (III)

The reaction is conveniently effected under conventional conditionssuitable for the oxidation of a primary alcohol to an aldehyde withoutfurther oxidation to the carboxylic acid, for example, using Dess-Martinperiodinane in a suitable solvent such as a halogenated hydrocarbon, forexample, dichloromethane, conveniently at about room temperature.

Compounds of formula (III) may be prepared by reaction of a compound offormula (V)

with ozone, followed by a reaction with a reducing agent such as sodiumborohydride (n is 1), or by reaction with a reducing agent such asborane.tetrahydrofuran complex, followed by hydrogen peroxide in thepresence of a base such as sodium hydroxide.

According to another general process (B), compounds of formula (I) maybe prepared by the reaction of a compound of formula (VI)

wherein LG is a suitable leaving group such as an alkyl- orarylsulfonyloxy group (e.g. mesylate or tosylate) or a halogen atom(e.g. bromine, chlorine or iodine); by reaction with an appropriatereactant to introduce a cyclic group as defined in relation to formula(I).

A particularly preferred compound of formula (VI) is that wherein thegroup LG is mesylate—i.e. the group —OSO₂CH₃.

According to another general process (C), compounds of formula (I) maybe prepared by the reaction of a compound of formula (VII) with acompound of formula (VIII)

preferably in the presence of a resin catalyst such as Amberlyst™ 15,and 3 Angstrom molecular sieves.

The reaction is conveniently effected in a suitable solvent such as ahalogenated hydrocarbon, for example, dichloromethane, conveniently atroom temperature.

According to another general process (C), compounds of formula (I)wherein R⁸ is other than hydrogen, may be prepared by the reaction of acompound of formula (XIV)

wherein Y is a suitable heteroatom or group such as an alkyl- orarylsulfinylimino group or an alkyl- or arylsulfonylimino group or anoxygen atom; by reaction with an appropriate nuclephilic reactant tointroduce a R⁷—(CH₂)_(n) group as defined in relation to formula (I).

Compounds of formula (XIV) may be prepared by methods well known to oneof ordinary skill in the art or by methods analogous to those describedherein.

Compounds of formula (VII) may be prepared by the reduction of acompound of formula (IX)

using conventional conditions such as sodium borohydride in the presenceof a transition metal catalyst such as cerium chloride hexahydrate, in asolvent such as alcohol, for example, ethanol; or using DIBAL in asolvent such as a halogenated hydrocarbon, for example, dichloromethane.

Compounds of formula (VIII) may be prepared from a compound of formula(X)

by reaction with a vinyl Grignard reagent such as R⁷(CH₂)_(n)MgBr,preferably in the presence of copper(I)iodide, and a suitable solventsuch as an ether, for example, tetrahydrofuran. This reaction iseffected at reduced temperature, for example, below −40° C. andpreferably at −78° C.

Compounds of formula (VI) and (X) are either known compounds or may beprepared by methods analogous to those described herein.

Compounds of formula (VI) may be prepared by conventional methods from,for example, a corresponding compound of formula (I) in which R⁷ is ahydroxyl group. Thus, for example, when LG is a mesylate group acorresponding compound of formula (I) in which R⁷ is hydroxyl may bereacted with methanesulfonyl chloride in the presence of a base, such astriethylamine. The reaction is conveniently effected in a solvent suchas a halogenated hydrocarbon, for example, dichloromethane.

It will be appreciated that the general methodology described above maybe adapted, using methods that are readily apparent to one of ordinaryskill in the art, in order to prepare further compounds of the presentinvention.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The exemplified compounds of this invention were tested by the methodsset out at pages 36 to 39 of International Patent Specification No. WO93/01165. The compounds were found to be active with IC₅₀ at the humanNK₁ receptor of less than 100 nM on said test method.

The following non-limiting Examples serve to illustrate the preparationof compounds of the present invention:

Description 14-Benzyloxycarbonyl-1-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-piperazinone

(2R,3R,4R)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)tetrahydro-2H-pyran-4-methylmethanesulfonate (WO 00/56727-A1; 2.32 g, 4.26 mmol) was added to asolution of 4-benzyloxycarbonylpiperazin-2-one (1.30 g, 5.54 mmol) andsodium hydride (60% dispersion in mineral oil, 170 mg, 4.26 mmol) inN,N-dimethylformamide (25 mL) and the mixture was stirred at 50° C. for16 hours. Further sodium hydride (60% dispersion in mineral oil, 85.2mg, 2.13 mmol) was added the mixture was stirred at 50° C. for 1.5hours. The mixture was cooled and the solvent was evaporated underreduced pressure. Water (50 mL) was added and the mixture was extractedwith ethyl acetate (3×100 mL). The combined organic fractions werewashed with brine (150 mL), dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with hexane/EtOAc (70:30increasing to 0:100) to give the title compound (2.06 g, 71%). m/z (ES⁺)683 (M+1), 425 (M+1-C₁₀H₈F₆O).

Description 2(2R,3S,4S)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-carboxaldehyde

A stirred cooled (−80° C.) solution of(2R,3S,4R)-2-[(1R)-1-[3,5-bis(triiluoromethyl)phenyl]ethoxy]-4-ethenyl-3-(4-fluorophenyl)tetrahydro-2H-pyran(WO 03/22839-A1; 2.35 g, 5.08 mmol) in methanol (15 mL) anddichloromethane (15 mL) was purged with oxygen. Ozone was bubbledthrough the solution until a blue coloration formed. The solution waspurged with oxygen and then with nitrogen. Dimethylsulfide (8 mL, 0.109mol) was added and the solution was stirred at room temperature for 16hours. The solvent was evaporated under reduced pressure and the residuewas purified by column chromatography on silica gel, eluting withhexane/EtOAc (100:0 increasing to 90:10), to give the title compound. ¹HNM (400 MHz, CDCl₃) δ 1.46 (3H, d J 6.6 Hz), 1.83 (1H, dddd J 13.2,12.5, 12.5, 5 Hz), 1.95 (1H, dm, J 13.4 Hz), 3.09 (1H, dd, J 12.4, 3.2Hz), 3.46 (1H, apparent tdd, J 12.1, 3.9, 2.5 Hz), 3.8 (1H, ddd, J 11.3,5, 1.4 Hz), 4.03 (1H, ddd, J 12.7, 11.6, 2.8 Hz), 4.50 (1H, d, J 3.2Hz), 4.89 (1H, q, J 6.6 Hz), 7.00 (2H, t, J 8.6 Hz), 7.23-7.20 (4H, m),7.64 (1H, s), and 9.45 (1H, d, J 2.4 Hz).

Description 3(2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4[(2Ror S)-oxiranyl]-3-phenyl-2H-pyran; and(2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2Sor R)-oxiranyl]-3-phenyl-2H-pyran (Isomers A and B)

Dimethylsulfoxide (10 mL) was added to sodium hydride (60% dispersion inmineral oil, 385 mg, 9.6 mmol) and the mixture was stirred at roomtemperature for 30 minutes. Tetrahydrofuran (20 mL) was added and themixture was cooled to −10° C. Trimethylsulfonium iodide (2.13 g, 10.4mmol) in dimethylsulfoxide (10 mL) was added and the mixture was stirredat 0° C. for 10 minutes.(2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde(WO 00/56727-A1; 3.58 g, 8.0 mmol) in tetrahydrofuran (10 mL) was addedand the mixture was stirred at 0° C. for 30 minutes, then at roomtemperature for 30 minutes. Water (100 mL) was added and the mixture wasextracted with ethyl acetate (3×100 mL). The combined organic fractionswere washed with water (4×100 mL) and brine (100 mL), dried (MgSO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel, eluting withhexane/EtOAc (85:15 increasing to 80:20), to give:

-   (2R, 3R,    4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2R    or S)-oxiranyl]-3-phenyl-2H-pyran (Isomer A; single diastereoisomer;    epoxide stereochemistry unassigned) as a colorless oil (1.37 g,    37%); ¹H NMR (500 MHz, CDCl₃) δ 7.67 (1H, s), 7.23 (5H, m), 7.01    (2H, m), 4.97 (1H, q, J 6.6 Hz), 4.28 (1H, d, J 8.4 Hz), 4.16 (1H,    br d, J 11 Hz), 3.53 (1H, br t, J 11 Hz), 2.65 (1H, dd, J 11.6, 8.4    Hz), 2.60 (1H, m), 2.34 (1H, t, J 4.5 Hz), 1.95 (1H, dd, J 4.5, 2.7    Hz), 1.84 (1H, br d, J 11 Hz), 1.68 (1H, m), 1.57 (1H, m), and 1.37    (3H, d, J 6.6 Hz); and-   (2R, 3R,    4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2S    or R)-oxiranyl]-3-phenyl-2H-pyran (Isomer B; single diastereoisomer;    epoxide stereochemistry unassigned) as a colorless oil (0.51 g,    14%); ¹H NMR (500 MHz, CDCl₃) δ 7.67 (1H, s), 7.27-7.20 (5H, m),    7.08 (2H, m), 4.96 (1H, q, J 6.6 Hz), 4.25 (1H, d, J 8.3 Hz), 4.13    (1H, br d, J 12 Hz), 3.54 (1H, br t, J 12 Hz), 2.68 (1H, m), 2.61    (1H, dd, J 11.5, 8.3 Hz), 2.50 (1H, t, J 4.6 Hz), 2.46 (1H, dd, J    4.6, 2.8 Hz), 2.03 (1H, m), 1.60 (1H, br d, J 12 Hz), 1.49 (1H, m),    and 1.37 (3H, d, J 6.6 Hz);    and a 1:1 mixture of Isomer A and Isomer B (1.16 g, 31%).

Description 4 (2R,3R,4R,αR orS)-α-{[(2-Hydroxyethyl)thio]methyl}-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol;and (2R,3R,4R,αS orR)-α-{[(2-Hydroxyethyl)thio]methyl}-2{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxytetrahydro-3-phenyl-2H-pyran-4-methanol

2-Mercaptoethanol (0.70 mL, 0.78 g, 10 mmol) was added to a degassedmixture of (2R,3R,4R)-2-{(1R)1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2R orS)-oxiranyl]-3-phenyl-2H-pyran and(2R,3R,4R)-2-{(1R)-1-[[3,5bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2Sor R)-oxiranyl]-3-phenyl-2H-pyran (Description 3; 1:1 mixture ofdiastereoisomers, 0.46 g, 1 mmol) and potassium hydroxide (0.56 g, 10mmol) in propan-2-ol (10 mL) and the mixture was heated under reflux for4 hours. The mixture was cooled and the solvent was evaporated underreduced pressure. Aqueous sodium hydroxide (1M, 20 mL) was added and themixture was extracted with diethyl ether (3×20 mL). The combined organicfractions were washed with aqueous sodium hydroxide (1M, 2×20 mL) andbrine (20 mL), dried (MgSO₄) and the solvent was evaporated underreduced pressure to give the title compound (1:1 mixture of alcoholepimers) as a yellow oil (0.54 g, 100%). ¹H NMR (500 MHz, CDCl₃) δ 7.66(1H, s), 7.26-7.23 (3H, m), 7.18 and 7.15 (2H, each s), 7.05 (2H, m),4.95 (1H, m), 4.25 and 4.23 (1H, each d, J 8.3 Hz), 4.18 (1H, m),3.62-3.53 (3H, m), 3.30 (1H, m), 2.90-1.51 (10H, m), and 1.36 (3H, d, J6.6 Hz).

Description 5 (2R,3R,4R,αR orS)-α-{[(2-Hydroxyethyl)sulfonyl]methyl}-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol;and (2R,3R,4R,αS orR)-α-{[(2-Hydroxyethyl)sulfonyl]methyl}-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol

3-Chlorobenzenecarboperoxoic acid (77%, 268 mg, 1.2 mmol) was added to asolution of (2R,3R,4R,αR orS)-α-{[(2-hydroxyethyl)thio]methyl}-2-{(1R)-1-3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanoland (2R,3R,4R,αS orR)-α-{[(2-hydroxyethyl)thio]methyl}-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol(Description 4; 1:1 mixture of alcohol epimers, 268 mg, 0.5 mmol) andsodium hydrogen carbonate (125 mg, 1.5 mmol) in dichloromethane (10 mL)and the mixture was stirred at room temperature for 1 hour. Saturatedaqueous sodium hydrogen carbonate (10 mL) was added and the mixture wasextracted with dichloromethane (3×20 mL). The combined organic fractionswere washed with saturated aqueous potassium carbonate (20 mL), dried(MgSO₄) and the solvent was evaporated under reduced pressure to givethe title compound (1:1 mixture of alcohol epimers) as a colorless foam(276 mg, 97%). ¹H NMR (500 MHz, CDCl₃) δ 7.66 (1H, s), 7.26 (3H, m),7.18 and 7.15 (2H, each s), 7.09-7.04 (2H, m), 4.94 (1H, m), 4.25 an4.24 (1H, each d, J 8.2 Hz), 4.19 (1H, m), 4.01-3.91 (3H, m), 3.54 (1H,m), 3.32-2.92 (4H, m), 2.88 and 2.54 (1H, each dd, J 11.5, 8.2 Hz),2.22-1.46 (5H, m), and 1.36 (3H, d, J 6.6 Hz).

Description 6(2R,3R,4R)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxyl]tetrahydro-3-phenyl-2H-pyran-4-methylBenzenesulfonate

Benzenesulfonyl chloride (1.036 L, 1.434 kg, 8.12 mol) was added slowlyto a stirred, cooled (−13° C.) solution of(2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]tetrahydro-3-phenyl-2H-pyran-4-methanol(WO 00/56727-A1; 2.60 kg, 5.80 mol) and 1,4-diazabicyclo[2.2.2]octane(1.041 kg, 9.28 mol) in ethyl acetate (26 L) and the resulting slurrywas allowed to warm to 0° C. Water (26 L) was added and the mixture wasstirred at 20° C. to 25° C. for 90 minutes. The layers were separatedand the organic layer was washed with hydrochloric acid (1M, 26 L) andaqueous sodium hydrogen carbonate (0.5M, 26 L). The solvent wasevaporated under reduced pressure to give the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.75 (2H, m), 7.66 (1H, br s), 7.62 (1H, m),7.48 (2H, m), 7.27-7.14 (5H, m), 6.89 (2H, m), 4.93 (1H, q, J 6.6 Hz),4.20 (1H, d, J 8.3 Hz), 4.12 (1H, ddd, J 11.9, 4.6, 1.8 Hz), 3.81 (1H,dd, J 9.8, 3.1 Hz), 3.62 (1H, dd, J 9.8, 6.9 Hz), 3.52 (1H, td, J 11.9,2.5 Hz), 2.51 (1H, dd, J 11.7, 8.3 Hz), 2.10 (1H, m), 1.77 (1H, m), 1.64(1H, m), and 1.34 (3H, d, J 6.6 Hz). ¹³C NMR (100 MHz, CDCl₃) δ 145.8,137.7, 136.0, 133.9, 131.7 (q, J_(CF) 33.2 Hz), 129.4, 128.9, 128.0,127.6, 126.4, 123.3 (q, J_(CF) 272.8 Hz), 121.6 (m), 102.4, 73.9, 72.0,64.7, 49.9, 39.9, 28.3, and 24.6.

Description 7(2R,3R,4R)-4-(Azidomethyl)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy]tetrahydro-3-phenyl-2H-pyran

Sodium azide (0.165 g, 2.55 mmol) was added to a solution of(2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]tetrahydro-3-phenyl-2H-pyran-4-methylbenzenesulfonate (Description 6; 0.5 g, 0.85 mmol) inN,N-dimethylformamide (10 mL) and the mixture was stirred at 50° C. for3 hours. The mixture was cooled and diethylether (50 mL) was added. Themixture was washed with water (×5), the organic layer was dried (MgSO₄)and the solvent was evaporated under reduced pressure to give the titlecompound (0.4 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ 1.36 (3H, d, J 6.7Hz), 1.59-1.69 (1H, m), 1.77-1.79 (1H, m), 1.93-2.04 (3H, m), 2.56 (1H,dd, J 8.4, 11.5 Hz), 2.94 (1H, dd, J 7.4, 12.1 Hz), 3.14 (1H, dd, J 3.1,12.1 Hz), 3.51-3.58 (1H, m), 4.09-4.19 (2H, m), 4.23 (1H, d, J 8.2 Hz),4.97 (1H, q, J 6.5 Hz), 7.01-7.04 (2H, m), 7.17 (2H, s), 7.23-7.26 (3H,m), and 7.66 (1H, s).

Description 8(2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)pheny]ethoxy]tetrahydro-3-phenyl-2H-pyran-4-methylamine

Palladium on carbon (10%, 50 mg) was added to a solution of(2R,3R,4R)-4-(azidomethyl)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]tetrahydro-3-phenyl-2H-pyran(Description 7; 0.4 g, 0.85 mmol) in tetrahydrofuran (10 mL) and themixture was stirred under hydrogen (1 atm.) for 1 hour. The mixture wasfiltered through Celite™ and the solvent was evaporated under reducedpressure to give the title compound (0.38 g, 100%). ¹H NMR (400 MHz,CDCl₃) δ 1.36 (3H, d, J 6.7 Hz), 1.48-1.65 (1H, m), 1.78-1.82 (2H, m),2.30-2.36 (1H, m), 2.44-2.52 (2H, m), 3.52-3.60 (1H, m), 4.09-4.27 (2H,m), 4.96 (1H, q, J 6.5 Hz), 7.01-7.04 (2H, m), 7.17 (2H, s), 7.22-7.26(3H, m), and 7.66 (1H, s).

EXAMPLE 11-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinoneHydrochloride

Palladium on carbon (10%, 240 mg) was added to a solution of4-benzyloxycarbonyl-1-[(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone(Description 1; 2.03 g, 2.98 mmol) in ethanol (20 mL) and the mixturewas shaken under hydrogen (50 psi) for 2 hours. Further palladium oncarbon (10%, 270 mg) was added and the mixture was shaken under hydrogen(50 psi) for a further 2.5 hours. The mixture was filtered throughCelite® and the solvent was evaporated under reduced pressure. Theresidue was triturated with dichloromethane to give 1-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone(1.53 g, 94%).

A portion (107 mg) was dissolved in methanol (1.5 mL) and poured onto anSCX cartridge (Varian Bond Elut™; 10 mL/500 mg). The cartridge waswashed with methanol (4×2 mL), then eluted with methanolic ammonia (2M,2×2 mL). The solvent was evaporated under reduced pressure, the residuewas dissolved in ethyl acetate and ethereal hydrogen chloride (1M, 200μl, 0.200 mmol) was added. The solvent was evaporated under reducedpressure and the residue was dried in vacuo to give the title compoundas a colorless solid (100 mg, 86%).

¹H NMR (360 MHz, CD₃OD) δ 1.33 (3H, d, J 6.6 Hz), 1.48 (1H, dq, J 12.1,4.6 Hz), 1.70-1.74 (1H, m), 2.31-2.40 (1H, m), 2.44-2.49 (1H, m), 2.95(1H, dd, J 13.8, 5.4 Hz), 3.12-3.20 (1H, m), 3.22-3.31 (2H, m),3.35-3.43 (2H, m), 3.54-3.69 (3H, m), 4.10 (1H, dd, J 11.7, 3.2 Hz),4.25 (1H, d, J 8.1 Hz), 5.01 (1H, q, J 6.4 Hz), 6.97 (2H, t, J 8.7 Hz),7.15-7.19 (2H, m), 7.31 (2H, s), and 7.74 (1H, s). m/z (ES⁺) 291(M+1-C₁₀H₈F₆O).

EXAMPLE 21-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-methylpiperazinoneHydrochloride

Sodium triacetoxyborohydride (153 mg, 0.728 mmol) was added to asolution of1-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone(Example 1; 100 mg, 0.182 mmol) and aqueous formaldehyde (38%, 52.5 μl,0.728 mmol) in dichloroethane (10 mL) and the mixture was stirred atroom temperature for 16 hours. Further aqueous formaldehyde (38%, 1.0mL, 13.7 mmol) and sodium triacetoxyborohydride (200 mg, 0.943 mmol)were added and the mixture was stirred at room temperature for 24 hours.The solvent was evaporated under reduced pressure and dichloromethane (5mL) and saturated aqueous sodium hydrogen carbonate (5 mL) were added.The layers were separated and the organic layer was poured onto an SCXcartridge (Varian Bond Elut™; 10 mL/500 mg). The cartridge was washedwith methanol (4×2 mL), then eluted with methanolic ammonia (2M, 2×2mL). The solvent was evaporated under reduced pressure, the residue wasdissolved in ethyl acetate and ethereal hydrogen chloride (1M, 146 μl,0.146 mmol) was added. The solvent was evaporated under reduced pressureand the residue was dried in vacuo to give the title compound (79.4 mg,74%). ¹H NMR (400 MHz, CD₃OD) δ 1.33 (3H, d, J 6.6 Hz), 1.46 (1H, dq, J12.3, 4.7 Hz), 1.66-1.70 (1H, m), 2.32-2.39 (1H, m), 2.42-2.49 (4H, m),2.72-2.81 (1H, br), 2.82-2.89 (3H, m), 3.11-3.17 (2H, m), 3.27-3.40 (2H,m), 3.46-3.50 (1H, m), 3.56-3.66 (1H, m), 4.07-4.11 (1H, m), 4.25 (1H,d, J 8.2 Hz), 5.00 (1H, q, J 6.6 Hz), 6.94-6.98 (2H, m), 7.14-7.17 (2H,m), 7.31 (2H, s), and 7.73 (1H, s). m/z (ES⁺) 563 (M+1), 305(M+1-C₁₀H₈F₆O).

EXAMPLE 31-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-ethylpiperazinoneHydrochloride

Prepared from1-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone(Example 1) and acetaldehyde according to the method of Example 2. ¹HNMR (400 MHz, CD₃OD) δ 1.14 (3H, t, J 7.2 Hz), 1.33 (3H, d, J 6.6 Hz),1.46 (1H, dq, J 12.4, 4.7 Hz), 1.69 (1H, dd, J 4.0, 2 Hz), 2.32-2.38(1H, m), 2.43-2.48 (1H, m), 2.62-2.74 (3H, br), 2.88 (2H, dd, J 13.7,4.9 Hz), 3.12-3.15 (2H, m), 3.22-3.39 (3H, m), 3.59 (1H, dt, J 12.2, 2.1Hz), 4.07-4.11 (1H, m), 4.25 (1H, d, J 8.2 Hz), 5.00 (1H, q, J 6.5 Hz),6.93-6.98 (2H, m), 7.14-7.18 (2H, m), 7.31 (2H, s), and 7.73 (1H, s).m/z (ES⁺) 577 (M+1), 319 (M+1-C₁₀H₈F₆O).

EXAMPLE 41-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-yl)methyl]-4(1-methylethyl)piperazinone

Prepared from1-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone(Example 1) and acetone according to the method of Example 2. ¹H NMR(360 MHz, CD₃OD) δ 0.99 (6H, d, J 6.5 Hz), 1.33 (3H, d, J 6.6 Hz), 1.45(1H, dq, J 12.3, 4.5 Hz), 1.65-4.70 (1H, m), 2.32-2.55 (4H, m), 2.63(1H, m), 2.88-3.03 (4H, m), 3.12-3.18 (1H, m), 3.27-3.23 (1H, m), 3.59(1H, dt, J 12.2, 2.1 Hz), 4.06-4.13 (1H, m), 4.23 (1H, d, J 8.1 Hz),5.01 (1H, q, J 6.5 Hz), 6.92-6.96 (2H, m), 7.12-7.17 (2H, m), 7.31 (2H,s), and 7.73 (1H, s). m/z (ES⁺) 591 (M+1), 333 (M+1-C₁₀H₈F₆O).

EXAMPLE 51-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-cyclohexylpiperazinone

Prepared from1-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone(Example 1) and cyclohexanone according to the method of Example 2. ¹HNMR (400 MHz, CD₃OD) δ 1.18-1.29 (6H, m), 1.33 (3H, d, J 6.6 Hz), 1.45(1H, dq, J 12.4, 4.7 Hz), 1.60-1.69 (2H, m), 1.78-1.80 (4H, m),2.20-2.25 (1H, m), 2.32-2.38 (1H, m), 2.40-2.47 (1H, m), 2.54-2.59 (1H,m), 2.90-3.01 (2H, m), 3.01-3.17 (2H, m), 3.27-3.32 (2H, m), 3.59 (1H,dt, J 12.2, 2.1 Hz), 4.06-4.12 (1H, m), 4.23 (1H, d, J 8.2 Hz), 5.00(1H, q, J 6.6 Hz), 6.94 (2H, t, J 8.8 Hz), 7.12-7.17 (2H, m), 7.30 (2H,s), and 7.73 (1H, s). m/z (ES⁺) 373 (M+1-C₁₀H₈F₆O).

EXAMPLE 61-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-(tetrahydropyran-4-yl)piperazinone

Prepared from1-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone(Example 1) and tetrahydro-4H-pyran-4-one according to the method ofExample 2. ¹H NMR (360 MHz, CD₃OD,) δ 1.35 (3H, d, J 11.8 Hz), 1.39-1.51(3H, m), 1.64-1.75 (3H, m), 2.33-2.48 (4H, m), 2.55-2.61 (1H, m),2.90-3.03 (3H, m), 3.11-3.18 (1H, m), 3.28-3.39 (4H, m), 3.59 (1H, dt, J11.0, 1.8 Hz), 3.94 (2H, dd, J 10.0, 3.3 Hz), 4.06-4.11 (1H, m), 4.24(1H, d, J 7.3 Hz), 5.00 (1H, q, J 5.9 Hz), 6.92-6.97 (2H, m), 7.12-7.16(2H, m), 7.31 (2H, s), and 7.73 (1H, s). m/z (ES⁺) 375 (M+1-C₁₀H₈F₆O).

EXAMPLE 71-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4(1-methylpiperidin-4-yl)piperazinone

Prepared from1-[((2R,3R,4R)-2-((1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone(Example 1) and 1-methyl-4-piperidinone according to the method ofExample 2. ¹H NMR (360 MHz, CD₃OD) δ 1.33 (3H, d, J 5.9 Hz), 1.43-1.55(5H, m), 1.64-1.68 (2H, br), 1.80-1.83 (2H, br), 2.12-2.28 (3H, m), 2.33(3H, s), 2.42-2.46 (2H, m), 2.55-2.63 (1H, m), 2.91-3.02 (4H, m),3.10-3.15 (2H, m), 3.56-3.62 (1H, m), 4.07 (1H, dd, J 10.7, 4.0 Hz),4.23 (1H, d, J 7.3 Hz), 5.00 (1H, q, J 6.2 Hz), 6.94 (2H, t, J 7.8 Hz),7.13-7.16 (2H, m), 7.30 (2H, s), and 7.73 (1H, s). m/z (ES⁺) 646 (M+1),388 (M+1-C₁₀H₈F₆O).

EXAMPLE 81-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-phenylpiperazinone

A degassed flask was charged withtris(dibenzylideneacetone)dipalladium(0) (0.88 mg, 0.96 μmol),2-(dicyclohexylphosphino)biphenyl (1.34 mg, 3.8 μmol) and sodiumtert-butoxide (51.5 mg, 0.536 mmol). Toluene (1.54 mL) then bromobenzene(80.7 μl, 0.77 mmol) were added, followed by1-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone(Example 1; 250 mg, 0.456 mmol) in toluene (2 mL) and the mixture wasstirred at 80° C. for 18 hours. Further bromobenzene (80.7 μl, 0.77mmol), sodium tert-butoxide (51.5 mg, 0.54 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.88 mg, 0.96 μmol) and2-(dicyclohexylphosphino)biphenyl (1.34 mg, 3.8 μmol) were added and themixture was stirred at 80° C. for 3 hours. The mixture was cooled,diluted with ether (100 mL) and fitered through Celite™. The solvent wasevaporated under reduced pressure and the residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂/EtOAc/NH₃(Aq.)(84:15:1) to give the title compound (165 mg, 58%). ¹H NMR (360 MHz,CD₃OD) δ 1.33 (3H, d, J 6.6 Hz), 1.48 (1H, dq, J 12.2, 4.7 Hz),1.64-1.69 (1H, m), 2.35-2.43 (1H, m), 2.44-2.49 (1H, m), 2.96 (1H, dd, J13.6, 5.2 Hz), 3.13-3.41 (5H, m), 3.54-3.70 (3H, m), 4.07 (1H, dd, J11.7, 3.2 Hz), 4.26 (1H, d, J 8.1 Hz), 5.00 (1H, q, J 6.5 Hz), 6.81-6.86(3H, m), 6.94 (2H, t, J 8.7 Hz), 7.15-7.25 (4H, m), 7.31 (2H, s), and7.73 (1H, s). m/z (ES⁺) 625 (M+1), 367 (M+1-C₁₀H₈F₆O).

EXAMPLE 91-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4yl)methyl]-4-(pyrid-3-yl)piperazinone

A degassed flask was charged withtris(dibenzylideneacetone)dipalladium(0) (3.2 mg, 3.5 μmol),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (8.3 mg, 13.3 μmol)and sodium tert-butoxide (103 mg, 1.07 mmol). Toluene (2 mL), then1-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone(Example 1; 250 mg, 0.456 mmol) in toluene (2 mL) were added, followedby 3-bromopyridine (103 μl, 1.06 mmol) and the mixture was stirred at80° C. for 16 hours. The mixture was cooled, diluted with ether (100 mL)and filtered through Celite™. The solvent, was evaporated under reducedpressure and the residue was purified by flash column chromatography onsilica gel, eluting with CH₂Cl₂/EtOAc/NH₃(Aq.) (792:8:1). The residuewas dissolved in methanol (1.5 mL) and poured onto an SCX cartridge(Varian Bond Elut™; 10 mL/500 mg). The cartridge was washed withmethanol (4×2 mL), then eluted with methanolic ammonia (2M, 2×2 mL). Thesolvent was evaporated under reduced pressure to give the title compound(131 mg, 46%). ¹H NMR (400 MHz, CDCl₃) δ 1.37 (3H, d, J 5.9 Hz),1.53-1.63 (1H, m), 1.68-1.72 (1H, m), 2.21-2.29 (1H, m), 2.48-2.53 (1H,m), 2.97 (1H, dd, J 12.3, 4.4 Hz), 3.16-3.30 (3H, m), 3.37-3.42 (1H, m),3.47-3.55 (2H, m), 3.69-3.80 (2H, m), 4.09-4.16 (2H, m), 4.92-4.97 (1H,m), 6.93-6.99 (2H, m), 7.04-7.10 (3H, m), 7.16-7.27 (3H, m), 7.68 (1H,s), 8.12 (1H, s), and 8.21 (1H, s). m/z (ES⁺) 368 (M+1-C₁₀H₈F₆O).

EXAMPLE 104-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]piperazinone

Prepared from(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde(WO 00/56727-A1) and piperazinone according to the method of Example 2.¹H NMR (360 MHz, CDCl₃) δ 7.66 (1H, s), 7.26-7.16 (5H, m), 7.01 (2H, m),6.00 (1H, br s), 4.92 (1H, q, J 6.5 Hz), 4.19 (1H, d, J 8.3 Hz), 4.12(1H, br d, J 12 Hz), 3.52 (1H, br t, J 12 Hz), 3.28-3.18 (2H, m), 3.07(1H, d, J 16.5 Hz), 2.77 (1H, d, J 16.5 Hz), 2.52-2.34 (3H, m),2.17-1.91 (4H, m), 1.45 (1H, m), and 1.36 (3H, d, J 6.5 Hz). m/z (ES⁺)531 (M+1), 273 (M+1-C₁₀H₈F₆O).

EXAMPLE 114[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone

Prepared from(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-carboxaldehyde(WO 03/022839-A1) and piperazinone according to the method of Example 2.¹H NMR (400 MHz, CDCl₃) δ 7.68 (1H, s), 7.17 (2H, s), 7.01-6.92 (4H, m),5.70 (1H, br s), 4.95 (1H, q, J 6.6 Hz), 4.14 (2H, m), 3.51 (1H, br t, J12 Hz), 3.30-3.20 (2H, m), 3.08 (1H, d, J 16.5 Hz), 2.78 (1H, d, J 16.5Hz), 2.48 (1H, m), 2.40 (2H, m), 2.15-1.85 (4H, m), 1.44 (1H, m), and1.37 (3H, d, J 6.5 Hz). m/z (ES⁺) 549 (M+1), 291 (M+1-C₁₀H₈F₆O).

EXAMPLE 124-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxyl}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-1-methylpiperazinone

Prepared from(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-carboxaldehyde(WO 03/022839-A1) and 1-methylpiperazinone according to the method ofExample 2. ¹H NMR (360 MHz, CDCl₃) δ 7.68 (1H, s), 7.17 (2H, s),7.00-6.92 (4H, m), 4.95 (1H, q, J 6.6 Hz), 4.14 (2H, m), 3.50 (1H, br t,J 12 Hz), 3.24 (1H, m), 3.14 (1H, m), 3.08 (1H, d, J 16.2 Hz), 2.89 (3H,s), 2.74 (1H, d, J 16.2 Hz), 2.50-2.37 (3H, m), 2.11 (1H, m), 1.99-1.85(3H, m), 1.42 (1H, m), and 1.36 (3H, d, J 6.6 Hz).

EXAMPLE 134-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxyl}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-1-ethylpiperazinone

Prepared from(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-carboxaldehyde(WO03/022839) and 1-ethylpiperazinone according to the method of Example2. ¹H NMR (360 MHz, CDCl₃) δ 7.68 (1H, s), 7.17 (2H, s), 7.00-6.92 (4H,m), 4.94 (1H, q, J 6.6 Hz), 4.14 (2H, m), 3.50 (1H, br t, J 12 Hz), 3.36(2H, q, J 7.2 Hz), 3.22 (1H, m), 3.13 (1H, m), 3.08 (1H, d, J 16.0 Hz),2.74 (1H, d, J 16.0 Hz), 2.50-2.37 (3H, m), 2.12 (1H, m), 2.00-1.86 (3H,m), 1.44 (1H, m), 1.36 (3H, d, J 6.6 Hz), and 1.08 (3H, t, J 7.2 Hz).m/z (ES⁺) 577 (M+1), 319 (M+1-C₁₀H₈F₆O).

EXAMPLE 144-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-1-phenylpiperazinone

Prepared from(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-carboxaldehyde(WO 03/022839-A1) and 1-phenylpiperazinone (Tet. Lett. 1998, 39,7459-7462) according to the method of Example 2. ¹H NMR (400 MHz, CDCl₃)δ 1.36 (3H, d, J 6.6 Hz), 1.44-1.52 (1H, m), 1.58-1.62 (1H, m),1.59-2.10 (2H, m), 2.19 (1H, dd, J 12.2, 10.0 Hz), 2.44 (1H, dd, 11.1,8.4 Hz), 2.53-2.58 (1H, m), 2.61-2.67 (1H, m), 3.26 (1H, d, J 16.4 Hz),2.93 (1H, d, J 16.4 Hz), 3.45-3.65 (3H, m), 4.15 (1H, d, J 8.4 Hz),4.11-4.17 (1H, m), 4.96 (1H, q, J 6.6 Hz), 6.93-7.03 (4H, m), 7.18 (2H,s), 7.19-7.27 (3H, m), 7.35-7.40 (2H, m), and 7.68 (1H, s). m/z (ES⁺)625 (M+1), 367 (M+1-C₁₀H₈F₆O).

EXAMPLE 154-((2R,3R,4R)-2-{1(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-1-(pyrid-3-yl)piperazinone

Prepared from(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-carboxaldehyde(WO 03/022839-A1) and 1-(3-pyridinyl)piperazinone (WO 01/44250-A1)according to the method of Example 2. ¹H NMR (360 MHz, CDCl₃) δ 1.36(3H, d, J 6.6 Hz), 1.42-1.58 (1H, m), 1.58-1.62 (1H, m), 1.94-2.10 (2H,m), 2.20 (1H, dd, J 12.2, 10.0 Hz), 2.44 (1H, dd, 11.1, 8.4 Hz),2.56-2.61 (1H, m), 2.64-2.70 (1H, m), 2.97 (1H, d, J 16.6 Hz), 3.27 (1H,d, J 16.6 Hz), 3.49-3.56 (2H, m), 3.63-3.68 (1H, m), 4.15 (1H, d, J 8.4Hz), 4.14-4.18 (1H, m), 4.96 (1H, q, J 6.6 Hz), 6.93-7.03 (4H, m), 7.18(2H, s), 7.31 (1H, dd, J 5.4, 4.8 Hz), 7.61-7.65 (1H, m), 7.68 (1H, s),8.48 (1H, dd, J 4.8, 1.4 Hz), and 8.53 (1H, d, J 2.3 Hz). m/z (ES⁺) 626(M+1), 368 (M+1-C₁₀H₈F₆O).

EXAMPLE 164-[((2R,3S,4S)-2-{1(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone

Prepared from(2R,3S,4S)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-carboxaldehyde(Description 2) and piperazinone according to the method of Example 2.¹H NMR (400 MHz, CDCl₈) δ 7.62 (1H, s), 7.18 (4H, m), 7.00 (2H, m), 5.80(1H, br s), 4.89 (1H, q, J 6.6 Hz), 4.38 (1H, d, J 2.2 Hz), 3.99 (1H, brt, J 12 Hz), 3.76 (1H, br d, J 12 Hz), 3.37 (1H, m), 3.28 (1H, m), 3.25(1H, d, J 16.6 Hz), 2.88 (1H, d, J 16.6 Hz), 2.65-2.40 (4H, m),2.15-2.00 (3H, m), 1.47 (1H, m), and 1.46 (3H, d, J 6.6 Hz). m/z (ES+)549 (M+1).

EXAMPLE 174-[((2R,3S,4S)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)]phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-1-methylpiperazinone

Prepared from(2R,3S,4S)-2-{(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-carboxaldehydeDescription 2) and 1-methylpiperazinone according to the method ofExample 2. ¹H NMR (400 MHz, CDCl₈) δ 7.62 (1H, s), 7.18 (4H, m), 7.00(2H, m), 4.89 (1H, q, J 6.6 Hz), 4.38 (1H, d, J 2.4 Hz), 3.98 (1H, br t,J 12 Hz), 3.75 (1H, br d, J 12 Hz), 3.34 (1H, m), 3.28 (1H, d, J 16.1Hz), 3.20 (1H, m), 2.94 (3H, s), 2.83 (1H, d, J 16.1 Hz), 2.65-2.45 (4H,m), 2.15-1.95 (3H, m), 1.46 (3H, d, J 6.6 Hz), and 1.45 (1H, m). m/z(ES⁺) 563 (M+1).

EXAMPLE 184-[((2R,3S,4S)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-1-ethylpiperazinone

Prepared from(2R,3S,4S)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-carboxaldehyde(Description 2) and 1-ethylpiperazinone according to the method ofExample 2. ¹H NMR (400 MHz, CDCl₃) δ 7.62 (1H, s), 7.17 (4H, m), 7.00(2H, m), 4.89 (1H, q, J 6.6 Hz), 4.38 (1H, d, J 2.4 Hz), 3.98 (1H, br t,J 12 Hz), 3.75 (1H, br d, J 12 Hz), 3.41 (2H, q, J 7.2 Hz), 3.30 (1H,m), 3.27 (1H, d, J 16.2 Hz), 3.18 (1H, m), 2.83 (1H, d, J 16.2 Hz),2.65-2.45 (4H, m), 2.15-1.95 (3H, m), 1.46 (3H, d, J 6.6 Hz), 1.45 (1H,m), and 1.12 (3H, t, J 7.2 Hz). m/z (ES⁺) 577 (M+1).

EXAMPLE 194-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(3,4-difluorophenyl)-2H-pyran-4-yl)methyl]thiomorpholine1,1-dioxide

Thiomorpholine 1,1-dioxide (15 mg, 0.11 mmol) was added to a solution of(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-(3,4-difluorophenyl)-2H-pyran-4-carboxaldehyde(WO 02/16344-A1, 25 mg, 0.052 mmol) in dichloromethane (5 mL) and themixture was stirred at room temperature for 1 hour. Sodiumtriacetoxyborohydride (16 mg, 0.075 mmol) was added and the mixture wasstirred at room temperature for 24 hours. Saturated aqueous sodiumhydrogen carbonate (5 mL) was added and the layers were separated. Theaqueous layer was extracted with dichloromethane (5 mL), the organicphases were combined and the solvent was evaporated under reducedpressure. The residue dissolved in DMSO (1 mL) and purified by massdirected HPLC (Waters X-Terra™ MS C-8 19×100 mm; water/acetonitrile/0.1%TFA gradient; collected fractions were evaporated to dryness in Genevac™HT-8 evaporator) to give the title compound as a colorless solid (19 mg,61%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.29 (4H, d, J 6.5 Hz), 1.86-1.75 (1H,m), 2.14-2.05 (2H, m), 2.42-2.26 (2H, m), 2.75-2.64 (1H, m), 2.96-2.86(1H, m), 3.03 (2H, d, J 14.7 Hz), 4.04-3.97 (1H, m), 4.32 (1H, d, J 8.4Hz), 5.06-4.99 (1H, m), 6.98 (1H, s), 7.26-7.17 (3H, m), 7.39 (2H, s),and 7.89 (1H, s). m/z (APci⁺) 602 (M+1).

EXAMPLE 204-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]thiomorpholine1.1-dioxide

Prepared from(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde(WO 00/56727-A1) and thiomorpholine 1,1-dioxide according to the methodof Example 19. ¹H NMR (400 MHz, DMSO-d₆) δ 1.27 (4H, t, J 6.9 Hz), 1.84(1H, d, J 13.2 Hz), 2.16-1.97 (3H, m), 2.34 (1H, t, J 9.5 Hz), 2.70 (2H,t, J 6.6 Hz), 2.87 (3H, s), 3.57 (1H, t, J 11.3 Hz) 4.01 (1H, dd, J 3.5,11.3 Hz), 4.34 (1H, d, J 8.4 Hz), 5.04 (1H, d, J 6.5 Hz), 7.21-7.11 (5H,m), 7.37 (2H, s), and 7.85 (1H, s). m/z (APci⁺) 566 (M+1).

EXAMPLE 211-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]-2-pyrrolidinone

Prepared from(2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-tetrahydro-3-phenyl-2H-pyran-4-methylbenzenesulfonate (Description 6) and 2-pyrrolidinone according to themethod of Description 1. ¹H NMR (400 MHz, CDCl₃) δ 1.35 (3H, d, J 6.7Hz), 1.49-1.59 (1H, m), 1.63 (1H, m), 1.70-1.82 (2H, m), 2.07-2.27 (3H,m), 2.48 (1H, dd, J 8.2, 11.3 Hz), 2.83 (1H, dd, J 5.1, 14.1 Hz), 3.04(1H, ddd, J 6.3, 8.2, 9.4 Hz), 3.12 (1H, ddd, J 6.3, 8.2, 9.4 Hz), 3.19(1H, dd, J 8.2, 13.7 Hz), 3.50 (1H, dt, J 2.7, 13.1 Hz), 4.12 (1H, ddd,J 2.0, 4.2, 11.7 Hz), 4.15 (1H, d, J 8.2 Hz), 4.93 (1H, q, J 6.3 Hz),7.05 (2H, m), 7.16 (2H, s), 7.20-7.27 (3H, m), and 7.66 (1H, s).

EXAMPLE 221-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]-2,5-pyrrolidinedione

Prepared from(2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-tetrahydro-3-phenyl-2H-pyran-4-methylbenzenesulfonate (Description 6) and 2,5-pyrrolidinedione according tothe method of Description 1. ¹H NMR (400 MHz, CDCl₃) δ 1.33 (3H, d, J6.7 Hz), 1.50 (1H, m), 1.62 (1H, m), 2.08-2.20 (4H, m), 2.46-2.59 (2H,m), 3.23 (1H, dd, J 5.9, 13.3 Hz), 3.44 (1H, dd, J 8.2, 13.7 Hz), 3.24(1H, dd, J 5.9, 14.1 Hz), 3.27 (1H, d, J 6.3 Hz), 3.52 (1H, dt, J 2.3,12.1 Hz), 4.05 (1H, d, J 7.8 Hz), 4.11 (1H, m), 4.88 (1H, q, J 6.7 Hz),7.04 (2H, m), 7.08 (2H, s), 7.16-7.25 (3H, m), and 7.63 (1H, s).

EXAMPLE 231-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]-2-imidazolidinone

Prepared from(2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-tetrahydro-3-phenyl-2H-pyran-4-methylbenzenesulfonate (Description 6) and 2-imidazolidinone according to themethod of Description 1. ¹H NMR (400 MHz, CDCl₃) δ 1.36 (3H, d, J 6.7Hz), 1.45-1.55 (1H, m), 1.74 (1H, m), 2.01-2.14 (2H, m), 2.48 (1H, dd, J8.2, 11.3 Hz), 2.76 (1H, dd, J 4.7, 14.1 Hz), 3.04 (1H, dd, J 8.6, 14.5Hz), 3.09-3.24 (4H, m), 3.52 (1H, dt, J 2.0, 11.7 Hz), 4.07 (1H, s),4.14 (1H, m), 4.17 (1H, d, J 8.2 Hz), 4.94 (1H, q, J 6.7 Hz), 7.05 (2H,m), 7.16 (2H, s), 7.20-7.25 (3H, m), and 7.66 (1H, s).

EXAMPLE 241-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]-3-methyl-2-imidazolidinone

Prepared from(2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-tetrahydro-3-phenyl-2H-pyran-4-methylbenzenesulfonate (Description 6) and 1-methyl-2-imidazolidinoneaccording to the method of Description 1. ¹H NMR (400 MHz, CDCl₂) δ 1.35(3H, d, J 6.7 Hz), 1.71-1.76 (1H, m), 2.04-2.11 (1H, m), 2.49 (1H, dd, J8.2, 11.7 Hz), 2.68 (3H, s), 2.78 (1H, d, J 14.1 Hz), 2.95-3.10 (5H, m),3.48-3.54 (1H, m), 4.11-4.14 (1H, m), 4.15 (1H, s), 4.17 (1H, s), 4.95(1H, q, J 6.7 Hz), 7.04-7.06 (2H, m), 7.16 (2H, s), 7.22 (3H, dd, J 3.1,3.1 Hz), and 7.65 (1H, s).

EXAMPLE 253-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]-1-methyl-2,4-imidazolidinedione

Prepared from(2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-tetrahydro-3-phenyl-2H-pyran-4-methylbenzenesulfonate (Description 6) and 1-methyl-2,4-imidazolidinedioneaccording to the method of Description 1.

¹H NMR (400 MHz, CDCl₃) δ 1.34 (3H, d, J 6.7 Hz), 1.50 (1H, m), 1.64(1H, m), 2.46-2.62 (2H, m), 2.73 (3H, s), 2.48 (1H, dd, J 8.2, 11.3 Hz),2.76 (1H, dd, J 4.7, 14.1 Hz), 3.24 (1H, dd, J 5.9, 14.1 Hz), 3.27 (1H,d, J 6.3 Hz), 3.39 (1H, dd, J 7.8, 13.7 Hz), 3.52 (1H, dt, J 2.4, 12.1Hz), 4.07 (1H, d, J 7.8 Hz), 4.12 (1H, dd, J 1.6, 4.3, 11.7 Hz), 4.88(1H, q, J 6.7 Hz), 7.07 (2H, m), 7.10 (2H, s), 7.17-7.23 (3H, m), and7.63 (1H, s).

EXAMPLE 262-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]-5-ethyl-1,2,5-thiadiazolidine1,1-dioxide

Prepared from(2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-tetrahydro-3-phenyl-2H-pyran-4-methylbenzenesulfonate (Description 6) and 2-ethyl-1,2,5-thiadiazolidine1,1-dioxide (J. Med. Chem. 1994, 37, 3023-3032) according to the methodof Description 1. ¹H NMR (400 MHz, CDCl₃) δ 1.20 (3H, t, J 7.4 Hz), 1.36(3H, d, J 6.7 Hz), 1.55 (1H, m), 1.62 (1H, m), 2.02 (1H, m), 2.04-2.15(1H, m), 2.45 (1H, dd, J 8.2, 11.4 Hz), 2.71-2.84 (2H, m), 2.95-3.07(3H, m), 3.09-3.20 (3H, m), 3.55 (1H, dt, J 2.3, 12.1 Hz), 4.15 (1H,ddd, J 1.6, 4.3, 11.7 Hz), 4.19 (1H, d, J 7.8 Hz), 4.94 (1H, q, J 6.7Hz), 7.05 (2H, m), 7.16 (2H, s), 7.21-7.26 (3H, m), and 7.65 (1H, s).

EXAMPLE 27 (5R orS)-5-((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-2,4-imidazolidinedione

A solution of(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifiluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde(WO 00/56727-A1; 350 mg, 0.78 mmol) and potassium cyanide (100 mg, 1.51mmol) in methanol (5 mL) was stirred at room temperature for 30 minutes.Ammonium carbonate (750 mg, 7.8 mmol) and water (5 mL) were added andthe mixture was stirred at 70° C. for 7 hours. The mixture was cooledand the solvent was evaporated under reduced pressure. Water was addedand the mixture was acidified with hydrochloric acid (6M) (CAUTION: HCNevolution). The mixture was extracted with ethyl acetate, the combinedorganic fractions were dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by preparative thinlayer chromatography on silica gel, eluting with CH₂Cl₂/MeOH (95:5). Theresidue was recrystallised from ethyl acetate to give the title compound(single diastereoisomer). ¹H NMR (400 MHz, DMSO-d₆) □ 1.20 (1H, m), 1.28(3H, d, J 6.7 Hz), 1.39-1.52 (1H, m), 2.30 (1H, m), 2.65 (1H, dd, J 8.6,12.5 Hz), 3.65 (1H, m), 4.01 (1H, dd, J 3.9, 11.4 Hz), 4.56 (1H, d, J8.6 Hz), 5.05 (1H, q, J 6.7 Hz), 7.23 (5H, m), 7.40 (2H, s), 7.86 (1H,m), and 8.13 (1H, s).

EXAMPLE 28 (3R orS)-3-((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-4-methylthiomorpholine1,1-dioxide

Triethylamine (0.072 mL, 0.52 mmol) was added to a stirred, cooled (−20°C.) solution of (2R,3R,4R,αR orS)-α-{[(2-hydroxyethyl)sulfonyl]methyl}-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanoland (2R,3R,4R, αS orR)-α-{[(2-hydroxyethyl)sulfonyl]methyl}-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol(Description 5; 1:1 mixture of alcohol epimers, 75 mg, 0.13 mmol) indichloromethane (2 mL) and the mixture was stirred at −20° C. for 5minutes. Methanesulfonyl chloride (0.03 mL, 0.388 mmol) was added slowlyand the mixture was stirred at −20° C. for 20 minutes. Water (5 mL) wasadded and the mixture was extracted with dichloromethane (2×5 mL). Thecombined organic fractions were washed with aqueous citric acid (10%, 10mL) then saturated aqueous sodium bicarbonate (10 mL), dried (MgSO₄) andthe solvent was evaporated under reduced pressure. The residue wasdissolved in methylamine (2M solution in methanol, 2 mL, 4 mmol), placedin a sealed tube and heated in a microwave oven at 130° C. for 10minutes. The mixture was cooled and the solvent was evaporated underreduced pressure. The residue was dissolved in methanol (1.5 mL) andpoured onto an SCX cartridge (Varian Bond Elut™; 10 mL/500 mg). Thecartridge was washed with methanol (4×2 mL), then eluted with methanolicammonia (2M, 2×2 mL). The solvent was evaporated under reduced pressure.The residue was purified by column chromatography on silica gel, elutingwith CH₂Cl₂/MeOH (100:0 increasing to 98:2), to give the title compound(single diastereoisomer) as a pale cream-coloured solid (7.3 mg, 10%).

¹H NMR (500 MHz, CD₃OD) δ 1.32 (3H, d, J 6.6 Hz), 1.50 (1H, m), 1.72(1H, dd, J 14.0, 2.4 Hz), 2.16 (1H, m), 2.21 (3H, s), 2.45-2.55 (3H, m),2.87 (1H, d, J 12.0 Hz), 2.99 (2H, dd, J 7.4, 2.2 Hz), 3.05-3.12 (2H,m), 3.65 (1H, dt, J_(d) 11.4, J_(t) 2.2 Hz), 4.10-4.13 (1H, m), 4.41(1H, d, J 7.5 Hz), 5.00 (1H, q, J 6.6 Hz), 7.13 (2H, dd, J 8.2, 1.6 Hz),7.20-7.26 (3H, m), 7.31 (2H, s), and 7.71 (1H, s). m/z (ES⁺) 566 (M+1),308 (M+1-C₁₀H₈F₆O).

EXAMPLE 292-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]isothiazolidine1,1-dioxide

3-Chloro-1-propanesulfonyl chloride (0.027 mL, 0.224 mmol) was added toa solution of(2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-tetrahydro-3-phenyl-2H-pyran-4-methylamine(Description 8; 100 mg, 0.224 mmol) and N-ethyldiisopropylamine (0.078mL, 0.448 mmol) in 1,2-dichloroethane (5 mL) and the mixture was stirredat room temperature for 3 days. Water was added and the layers wereseparated. The organic fraction was dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified bypreparative thin layer chromatography on silica gel, eluting withEtOAc/hexane (50:50) and the residue was recrystallised from hexane. Thesolid was collected, dissolved in 1,2-dichloroethane and aqueous sodiumhydroxide solution (50%) and tetra-n-butylammonium bromide (3 mg) wereadded. The mixture was stirred at room temperature for 2 hours. Thelayers were separated, the organic fraction was dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby preparative thin layer chromatography on silica gel, eluting withEtOAc/hexane (50:50) to give the title compound. ¹H NMR (400 MHz, CDCl₃)δ 1.36 (3H, d, J 6.7 Hz), 1.52 (1H, m), 1.95 (1H, m), 2.00-2.12 (1H, m),2.19 (2H, m), 2.44 (1H, dd, J 8.2, 11.3 Hz), 2.68 (1H, dd, J 3.9, 14.1Hz), 2.82 (1H, dd, J 9.0, 13.7 Hz), 2,87-3.13 (4H, m), 2.95-3.07 (3H,m), 3.09-3.20 (3H, m), 3.54 (1H, dt, J 2.4, 12.1 Hz), 4.15 (1H, ddd, J1.6, 4.7, 12.1 Hz), 4.19 (1H, d, J 7.8 Hz), 4.94 (1H, q, J 6.7 Hz), 7.06(2H, m), 7.16 (2H, s), 7.21-7.28 (3H, m), and 7.65 (1H, s).

1-21. (canceled)
 22. A compound of the formula (I):

wherein: R¹ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy,fluoroC₁₋₆alkyl, fluoroC₁₋₆alkoxy, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, NO₂, CN, SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a),CONR^(a)R^(b), C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₄alkyl substituted byC₁₋₄alkoxy, wherein R^(a) and R^(b) each independently representhydrogen or C₁₋₄alkyl; R² is hydrogen, halogen, C₁₋₆alkyl,fluoroC₁₋₆alkyl or C₁₋₆alkoxy substituted by C₁₋₄alkoxy; R³ is hydrogen,halogen or fluoroC₁₋₆alkyl; R⁴ is hydrogen, halogen, C₁₋₆alkyl,C₁₋₆alkoxy, fluoroC₁₋₆alkyl, fluoroC₁₋₆alkoxy, hydroxy, NO₂, CN, SR^(a),SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl, C₂₋₆alkynyl orC₁₋₄alkyl substituted by C₁₋₄alkoxy; R⁵ is hydrogen, halogen, C₁₋₆alkyl,fluoroC₁₋₆alkyl or C₁₋₆alkoxy substituted by C₁₋₄alkoxy; R⁶ representshydrogen or a C₁₋₄alkyl group which is unsubstituted or substituted by ahydroxy group; R⁷ represents a 5- or 6-membered carbonyl or sulfonylcontaining cyclic group comprising from 0 to 3 nitrogen ring atoms, from0 to 1 oxygen ring atom and from 0 to 1 sulfur ring, wherein said ringis unsubstituted or substituted at any substitutable position by one ormore substituents selected from ═O, halogen, hydroxy, R¹¹, R¹², SR^(f),SO₂R^(g), COR^(a), CO₂R^(a), CONR⁹R¹⁰, -ZNR⁹R¹⁰, benzyl, C₁₋₄alkyl,hydroxyC₁₋₄alkyl, fluoroC₁₋₄alkyl, chloroC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, C₃₋₇cycloalkoxy,C₃₋₇cycloalkoxyC₁₋₄alkyl, C₁₋₄alkoxy, fluoroC₁₋₄alkoxy,hydroxyC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkoxy, aryl, arylC₁₋₄alkyl,heteroaryl, heteroarylC₁₋₄alkyl or a 5- or 6-membered ring containing inthe ring one oxygen atom or N(C₁₋₆alkyl), wherein R^(f) is C₁₋₄alkyl oraralkyl or aryl and R^(g) is C₁₋₄alkyl, aryl, arylC₁₋₄alkyl or NR⁹R¹⁰;R⁸ represents hydrogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl, hydroxy, C₁₋₆alkoxy,hydroxyC₁₋₆alkyl NR⁹R¹⁰, CONR⁹R¹⁰ or SO₂R^(g); R⁹ is hydrogen,C₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, fluoroC₁₋₄alkyl,C₂₋₄alkyl substituted by a C₁₋₄alkoxy or hydroxyl group, or R⁹ is a fivemembered or six membered nitrogen-containing heteroaromatic ring aspreviously defined; R¹⁰ is hydrogen or C₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, fluoroC₁₋₄alkyl or C₂₋₄alkyl substituted by aC₁₋₄alkoxy or hydroxyl group; or R⁹, R¹⁰ and the nitrogen atom to whichthey are attached form a heteroaliphatic ring of 4 to 7 ring atoms,unsubstituted or substituted by one or two groups selected from hydroxy,COR^(e), CO₂R^(e), C₁₋₄alkyl unsubstituted or substituted by aC₁₋₄alkoxy or hydroxyl group, or C₁₋₄alkoxy unsubstituted or substitutedby a C₁₋₄alkoxy or hydroxyl group, or a five membered or six memberednitrogen-containing heteroaromatic ring as previously defined, or saidheteroaliphatic ring is substituted by a spiro-fused lactone ring, andsaid heteroaliphatic ring optionally containing a double bond, whichheteroaliphatic ring may contain an oxygen or sulphur ring atom, a groupS(O) or S(O)₂ or a second nitrogen atom which will be part of a NH orNR^(d) moiety, where R^(d) is C₁₋₄alkyl unsubstituted or substituted byhydroxy or C₁₋₄alkoxy; or R⁹, R¹⁰ and the nitrogen atom to which theyare attached form a non-aromatic azabicyclic ring system of 6 to 12 ringatoms; or R⁹, R¹⁰ and the nitrogen atom to which they are attached forma heteroaliphatic ring of 4 to 7 ring atoms to which is fused a benzenering or a five membered or six membered nitrogen-containingheteroaromatic ring optionally containing 1, 2 or 3 additionalheteroatoms selected from N, O and S; R¹¹ and R¹² each independentlyrepresent hydrogen, hydroxy, COR^(e), CO₂R^(e), C₁₋₄alkyl unsubstitutedor substituted by a C₁₋₄alkoxy or hydroxyl group, or C₁₋₄alkoxyunsubstituted or substituted by a C₁₋₄alkoxy or hydroxyl group; or, whenthey are attached to the same carbon atom, R¹¹ and R¹² may togetherrepresent ═O, ═CHCO₂R^(a), —O(CH₂)_(m)O—, —CH₂O(CH₂)_(k)—,—CH₂OCH₂C(O)—, —CH₂OCH₂CH(OH)—, —CH₂OCH₂C(CH₃)₂—, —CH₂OC(CH₃)₂CH₂—,—C(CH₃)₂OCH₂CH₂—, —CH₂C(O)OCH₂—, —OC(O)CH₂CH₂—, —C(O)OCH₂CH₂—,—C(O)OC(CH₃)₂CH₂—, —C(O)OCH₂C(CH₃)₂—, —OCH₂(CH₂)_(k)—, —OC(CH₃)₂CH₂CH₂—,—OCH₂C(CH₃)₂CH₂—, —OCH₂CH₂C(CH₃)₂—, —OCH₂CH═CHCH₂—, —OCH₂CH(OH)CH₂CH₂—,—OCH₂CH₂CH(OH)CH₂—, —OCH₂C(O)CH₂CH₂—, —OCH₂CH₂C(O)CH₂—, or a group ofthe formula:

or, where they are attached to adjacent carbon atoms, R¹¹ and R¹² maytogether represent —OCH₂CH₂— or —OCH₂CH(OH)—, or R¹¹ and R¹² maytogether form a fused benzene ring; or, R¹¹ and R¹² together form aC₁₋₂alkylene bridge across the pyrrolidine, piperidine, morpholine orpiperazine ring to which they are attached; R¹³ represents hydrogen,phenyl, benzyl, pyridyl, tetrahydropyranyl, piperidinyl, N-substitutedpiperidinyl (where the N-substituent is C₁₋₆alkyl), C₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, —SO₂C₁₋₄alkyl or C₂₋₄alkylsubstituted by a C₁₋₄alkoxy or hydroxyl group; R¹⁴ represents hydrogen,halogen, hydroxy, C₁₋₄alkyl, hydroxyC₁₋₄alkyl or fluoroC₁₋₄alkyl; R¹⁵and R¹⁶ each independently represent hydrogen, halogen, C₁₋₆alkyl,CH₂OR^(c), oxo, CO₂R^(a) or CONR^(a)R^(b) where R^(a) and R^(b) are aspreviously defined and R^(c) represents hydrogen, C₁₋₆alkyl or phenyl; Zrepresents a bond, C₁₋₆alkylene or C₃₋₆cycloalkylene; k is 1, 2 or 3; mis 1 or 2; and n is zero, 1 or 2; with the proviso that when n is zeroand R⁸ is hydrogen, R⁷ does not represent a C-linked nitrogen-containingring of the formula:

wherein: A represents NR¹³, and B represents a bond, CH₂, NR¹³ or O,wherein one or both hydrogen atoms in said CH₂ moiety may be replacedwith one or both of R¹¹ and R¹², or alternatively, one of the hydrogenatoms in said CH₂ moiety together with a hydrogen atom from an adjacentcarbon are replaced by a double bond; or A is O, and B is NR¹³; and R¹¹and R¹² together represent ═O; and pharmaceutically acceptable saltsthereof.
 23. The compound of claim 22 wherein R¹ is hydrogen, C₁₋₄alkyl,C₁₋₄alkoxy, halogen or CF₃.
 24. The compound of claim 22 wherein R² ishydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.
 25. The compound ofclaim 22 wherein R³ is hydrogen, fluorine, chlorine or CF₃.
 26. Thecompound of claim 22 wherein R⁴ is hydrogen or fluorine.
 27. Thecompound of claim 22 wherein R⁵ is hydrogen, fluorine, chlorine or CF₃.28. The compound of claim 22 wherein R is C₁₋₄alkyl optionallysubstituted by hydroxy.
 29. The compound of claim 22 wherein R⁷ is acyclic group selected from the group consisting of:

wherein any of said cyclic groups is unsubstituted or substituted by oneor more groups as defined in claim
 22. 30. The compound of claim 22wherein R⁷ is a cyclic group selected from the group consisting of:

wherein any of said cyclic groups is unsubstituted or substituted by oneor more groups as defined in claim
 1. 31. The compound of claim 22wherein R⁸ is hydrogen or methyl.
 32. The compound of claim 22 whereinR¹² is hydrogen, hydroxy, C₁₋₂alkyl substituted by hydroxy, C₁₋₄alkoxyor CO₂R^(e), where R^(e) is hydrogen, methyl ethyl or benzyl.
 33. Thecompound of claim to 11 wherein R¹³ represents hydrogen, methyl orethyl.
 34. The compound of claim 22 wherein R¹⁵ is hydrogen and R¹⁶ ishydrogen.
 35. The compound of claim 22 wherein n is zero or
 1. 36. Thecompound of claim 22 of the formula (Ia):

wherein: A¹ is fluorine or CF₃; A² is fluorine or CF₃; A³ is fluorine orhydrogen; A⁴ is fluorine or hydrogen; A⁵ is methyl; or apharmaceutically acceptable salt thereof.
 37. A compound which isselected from the group consisting of:1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone;1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-methylpiperazinone;1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-ethylpiperazinone;1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-(1-methylethyl)piperazinone;1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-cyclohexylpiperazinone;1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-(tetrahydropyran-4-yl)piperazinone;1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-(1-methylpiperidin-4-yl)piperazinone;1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-phenylpiperazinone;1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-4-(pyrid-3-yl)piperazinone;4-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]piperazinone;4-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-1-methylpiperazinone;4-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-1-ethylpiperazinone;4-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-1-phenylpiperazinone;4-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-1-(pyrid-3-yl)piperazinone;4-[((2R,3S,4S)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]piperazinone;4-[((2R,3S,4S)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-1-methylpiperazinone;4-[((2R,3S,4S)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(4-fluorophenyl)-2H-pyran-4-yl)methyl]-1-ethylpiperazinone;4-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-(3,4-difluorophenyl)-2H-pyran-4-yl)methyl]thiomorpholine1,1-dioxide;4-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]thiomorpholine1,1-dioxide;1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]-2-pyrrolidinone;1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]-2,5-pyrrolidinedione;1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]-2-imidazolidinone;1-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]-3-methyl-2-imidazolidinone;3-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]-1-methyl-2,4-imidazolidinedione;2-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]-5-ethyl-1,2,5-thiadiazolidine1,1-dioxide; (5R orS)-5-((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-2,4-imidazolidinedione;(3R orS)-3-((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-4-methylthiomorpholine1,1-dioxide;2-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)methyl]isothiazolidine1,1-dioxide; or a pharmaceutically acceptable salt thereof.
 38. Apharmaceutical composition comprising the compound of claim 22 and atleast one pharmaceutically acceptable carrier or excipient.
 39. A methodfor the treatment of pain or inflammation, migraine, emesis,postherpetic neuralgia, depression or anxiety, which method comprisesadministration to a patient in need thereof of a therapeuticallyeffective amount of the compound of claim
 22. 40. A method for theprevention of pain or inflammation, migraine, emesis, postherpeticneuralgia, depression or anxiety, which method comprises administrationto a patient in need thereof of a therapeutically effective amount ofthe compound of claim 22.